Foregut microbiome in development of esophageal adenocarcinoma

描述（由申请人提供）：食管腺癌（EA）是一种与胃食管反流病（GERD）引起的胃灼热相关的癌症类型，在过去30年中增加了6倍，这不能用通常的环境或宿主因素来解释。EA是一系列GERD相关疾病的最终结果，之前是反流性食管炎（RE）和巴雷特食管（BE）。我们对老年男性退伍军人的初步研究发现，食管中存在两种类型的微生物。携带II型微生物群的患者患食管炎和BE的可能性是携带I型微生物群的患者的>15倍。在一项小规模的研究中，我们还发现3例EA病例中有3例携带II型生物群。这些发现为理解最近EA发病率的激增开辟了一条新途径。我们的长期目标是确定GERD序列的原因。待检验的假设是，前肠微生物组的变化与EA及其前体、GERD序列中的RE和BE相关。我们将研究老年男性受试者的发现是否也适用于年轻和女性受试者。我们将进行一项病例对照研究，以证明GERD序列每个阶段的微生物组-疾病相关性，并通过两个特定目标分析微生物组沿着疾病进展至EA的变化趋势。目的1是对前肠微生物组进行全面的人群调查，并证明其与GERD序列的相关性。此外，还将检查食管微生物群与上游（口腔）和下游（胃）前肠微生物群之间的空间关系以及微生物群-疾病关联的时间稳定性。目的二是确定食管远端宏基因组并证明其与GERD序列的相关性。详细分析将包括路径-疾病和基因-疾病关联。病原菌、真菌和病毒，如果被鉴定出来，也将与疾病相关。前肠微生物组和GERD序列之间的显著关联，如果得到证实，将是最终测试是否需要异常微生物组来发展EA的表型变化序列的第一步。如果EA及其前体代表一种微生态疾病，那么治疗GERD的原因可能成为可能，例如，通过使用抗生素，益生菌或益生元使微生物群正常化。GERD的病因治疗可以防止其进展，并扭转目前EA发病率增加的趋势。公共卫生相关性：食管腺癌是一种与胃食管反流病（GERD）引起的胃灼热有关的癌症，在过去的30年里已经增加了六倍，这不能用通常的环境或宿主因素来解释。我们打算在GERD的不同阶段描述食管微生物组（食管的天然细菌种群）的变化。如果GERD代表一种微生物组相关疾病，则有可能设计新的抗生素或益生菌治疗策略来预防GERD并扭转目前食管腺癌发病率上升的趋势。

DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years, which cannot be explained by the usual environmental or host factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett's esophagus (BE). Our preliminary study in elderly male veterans found two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small-scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will examine whether the finding in elderly male subjects also applies to younger as well as female subjects. We will conduct a case control study to demonstrate the microbiome-disease association in every stage of GERD sequence as well as analyze the trend in changes in the microbiome along disease progression toward EA, by two specific aims. Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA. PUBLIC HEALTH RELEVANCE: Esophageal adenocarcinoma, the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has jumped six folds in the past 30 years, which cannot be explained by the usual environmental or host factors. We intend to characterize the change in the esophageal microbiome (the native bacterial population of the esophagus), in patients at various stages in GERD. If GERD represents a microbiome-related disease, it could be possible to design new antibiotic or probiotic treatment strategies to prevent GERD and reverse the current trend of increasing rate of esophageal adenocarcinoma.